2,6-diisopropylphenol, commonly known as “Propofol”, is a short-acting, intravenously administered hypnotic agent. It is used as a general anesthetic or as a soporifacient for mechanically ventilated adults, and for procedural sedation.
2,6-diisopropylphenol has several mechanisms of action, both through potentiation of GABAA receptor activity, thereby slowing the channel-closing time and also acting as a sodium channel blocker. Recent research has also suggested that the endocannabinoid system may contribute significantly to anesthetic action of 2,6-diisopropylphenol and to its unique properties. 2,6-diisopropylphenol is highly protein-bound in vivo and is metabolized by conjugation in the liver. Its rate of clearance exceeds hepatic blood flow, suggesting an extra-hepatic site of elimination as well.
Generally, 2,6-diisopropyl phenol is administered intravenously; hence the purity requirement is very high. For most purposes, ideal purity for 2,6-diisopropylphenol has to be more then 99.9%. The commercially available 2,6-diisopropylphenol is about 97% pure. The said product typically contains unreacted phenol, one or more monoalkylphenols, one or more dialkylphenol isomers other than the desired 2,6-dialkylphenol isomer.
A myriad of patents/patent applications have been filed across globe for preparation and purification of 2,6-diisopropylphenol, namely U.S. Pat. No. 5,696,300, U.S. Pat. No. 4,275,248, U.S. Pat. No. 3,029,276, WO2005033279, CN1197055, WO200034218, EP169359, U.S. Pat. No. 3,367,981, U.S. Pat. No. 3,271,314, U.S. Pat. No. 3,766,276, SU170505, U.S. Pat. No. 2,831,898, U.S. Pat. No. 2,207,753, GB1318100, U.S. Pat. No. 4,391,998, U.S. Pat. No. 4,774,368, U.S. Pat. No. 5,589,598 and U.S. Pat. No. 6,362,234.
EP0511947 discloses purification of 2,6-diisopropylphenol (Propofol). Accordingly, Propofol obtained by alkylation of propene with phenol is purified by crystallization as such at a temperature from −20° C. to −10° C. In an alternate method, said patent discloses purification of Propofol by crystallization from non-polar solvents, such as, petrol ether or hexane. The solvent residues are then removed either by distillation or evaporation and the product itself is recovered as a single fraction in the distillation. However, such a procedure is not well suited for use in a large scale commercial operation.
U.S. Pat. No. 5,264,085 describe a method of continuously separating components of a hydrous phenol mixture containing methanol by distillation. The method involves recovering methanol from the top of a single distillation column, dragging water containing phenols as a side stream from the recovery section of the distillation column and the dehydrated phenols as a bottom product.
U.S. Pat. No. 5,705,039 discloses a process for the purification of impure 2,6-diisopropylphenol which comprises: a) subjecting the impure 2,6-diisopropylphenol to a first continuous distillation in a single distillation column in an inert environment to produce (i) a first overhead distillate of impurities boiling below the boiling point of 2,6-diisopropylphenol at the prevailing pressure and (ii) first column bottoms enriched in 2,6-diisopropylphenol; b) collecting, cooling and storing the first column bottoms while continuously maintaining them in an inert environment; c) discontinuing the first continuous distillation; and d) subjecting said first column bottoms to a second continuous distillation in an inert environment in the same single distillation column to produce a second overhead distillate composed of purified 2,6-diisopropylphenol the process is however tedious and not economically viable.
U.S. Pat. No. 5,591,311 describes the process of purification of 2,6-diisopropylphenol which involves washing the mixture with aqueous alkali metal hydroxide solution in an inert atmosphere and separating the aqueous and organic phases, washing the resulting organic phase with water, and then subjecting the water-washed organic phase to distillation in an inert environment to recover purified diisopropylphenol(DIP).
U.S. Pat. No. 5,589,598 describes a process for the purification of 2,6-diisopropylphenol (Propofol) by transformation of the crude propofol into its ester with a carboxylic or sulphonic acid, followed by crystallization and hydrolysis.
Propofol is generally prepared from phenol and propene by Friedel-Crafts-alkylation, whereby in the reaction, besides the desired product, small amounts of other isomers and phenol derivatives are formed thus affecting the purity of the product. The major contaminants being 2,4- and 2,5-diisopropyl phenol, 2,4,6-triisopropyl phenol, and 1-isopropoxy-2,4-diisopropylbenzene having small differences in their boiling points.
In view of the above drawbacks in the preparation of Propofol there remains a need to develop a process for the preparation of 2,6-diisopropylphenol (Propofol) with high purity suitable for pharmaceutical use and which is simple, economical for large scale manufacturing.